Colchicine: A Possible COVID-19 Long haul Cardiac Therapy

Last Updated: December 16, 2021

Last Updated: December 16, 2021

Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout, recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been shown to potentially reduce the risk of cardiovascular events in those with coronary artery disease.2 Colchicine has several potential mechanisms of action, including reducing the chemotaxis of neutrophils, inhibiting inflammasome signaling, and decreasing the production of cytokines, such as interleukin-1 beta.3 When colchicine is administered early in the course of COVID-19, these mechanisms could potentially mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory properties coupled with the drug’s limited immunosuppressive potential, favorable safety profile, and widespread availability have prompted investigation of colchicine for the treatment of COVID-19.

Recommendations

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of colchicine for the treatment of nonhospitalized patients with COVID-19, except in a clinical trial (BIIa).
  • The Panel recommends against the use of colchicine for the treatment of hospitalized patients with COVID-19 (AI).

Rationale

For Nonhospitalized Patients With COVID-19

COLCORONA, a large randomized placebo-controlled trial that evaluated colchicine in outpatients with COVID-19, did not reach its primary efficacy endpoint of reducing hospitalizations and death.4 However, in the subset of patients whose diagnosis was confirmed by a positive SARS-CoV-2 polymerase chain reaction (PCR) result from a nasopharyngeal (NP) swab, a slight reduction in hospitalizations was observed among those who received colchicine.

PRINCIPLE, another randomized, open-label, adaptive-platform trial that evaluated colchicine versus usual care, was stopped for futility when no significant difference in time to first self-reported recovery from COVID-19 between the colchicine and usual care recipients was found.5

The PRINCIPLE trial showed no benefit of colchicine, and the larger COLCORONA trial failed to reach its primary endpoint, found only a very modest effect of colchicine in the subgroup of patients with positive SARS-CoV-2 PCR results, and reported more gastrointestinal adverse events in those receiving colchicine. Therefore, the Panel recommends against the use of colchicine for the treatment of COVID-19 in nonhospitalized patients, except in a clinical trial (BIIa).

For Hospitalized Patients With COVID-19

In the RECOVERY trial, a large randomized trial in hospitalized patients with COVID-19, colchicine demonstrated no benefit with regard to 28-day mortality or any secondary outcomes.6 Based on the results from this large trial, the Panel recommends against the use of colchicine for the treatment of COVID-19 in hospitalized patients (AI).

Clinical Data for COVID-19

Colchicine in Nonhospitalized Patients With COVID-19

The COLCORONA Trial

The COLCORONA trial was a contactless, double-blind, placebo-controlled, randomized trial in outpatients who received a diagnosis of COVID-19 within 24 hours of enrollment. Participants were aged ≥70 years or aged ≥40 years with at least 1 of the following risk factors for COVID-19 complications: body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were randomized 1:1 to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by Day 30. Participants reported by telephone the occurrence of any study endpoints at 15 and 30 days after randomization; in some cases, clinical data were confirmed or obtained by medical chart reviews.4

Results

  • The study enrolled 4,488 participants.
  • The primary endpoint occurred in 104 of 2,235 participants (4.7%) in the colchicine arm and 131 of 2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
  • There were no statistically significant differences in the secondary outcomes between the arms.
  • In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by PCR testing of an NP specimen (93% of those enrolled), those in the colchicine arm were less likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup of patients with PCR-confirmed SARS-CoV-2 infection, there were fewer hospitalizations (a secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of patients; OR 0.75; 95% CI, 0.57–0.99).
  • More participants in the colchicine arm experienced gastrointestinal adverse events, including diarrhea which occurred in 13.7% of colchicine recipients versus 7.3% of placebo recipients (P < 0.0001). Unexpectedly, more pulmonary emboli were reported in the colchicine arm than in the placebo arm (11 events [0.5% of patients] vs. 2 events [0.1% of patients]; P= 0.01).

Limitations

  • Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target enrollment, which may have limited the study’s power to detect differences for the primary outcome.
  • There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
  • Some patient-reported clinical outcomes were potentially misclassified.

The PRINCIPLE Trial

PRINCIPLE is a randomized, open-label, platform trial that evaluated colchicine in symptomatic, nonhospitalized patients with COVID-19 who were aged ≥65 years or aged ≥18 years with comorbidities or shortness of breath, and who had symptoms for ≤14 days. Participants were randomized to receive colchicine 0.5 mg daily for 14 days or usual care. The coprimary endpoints, which included time to first self-reported recovery or hospitalization or death due to COVID-19 by Day 28, were analyzed using a Bayesian model. Participants were followed through symptom diaries that they completed online daily; those who did not complete the diaries were contacted by telephone on Days 7, 14, and 29. The investigators developed a prespecified criterion for futility, specifying a clinically meaningful benefit in time to first self-reported recovery as a hazard ratio ≥1.2, corresponding to about 1.5 days of faster recovery in the colchicine arm.

Results

  • The study enrolled 4,997 participants: 212 participants were randomized to receive colchicine; 2,081 to receive usual care alone; and 2,704 to receive other treatments.
  • The prespecified primary analysis included participants with SARS-CoV-2 positive test results (156 in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments arm).
  • The trial was stopped early because the criterion for futility was met; the median time to self-reported recovery was similar in the colchicine arm and the usual care arm (HR 0.92; 95% CrI, 0.72–1.16).
  • Analyses of self-reported time to recovery and hospitalizations or death due to COVID-19 among concurrent controls also showed no significant differences between the colchicine and usual care arms.
  • There were no statistically significant differences in the secondary outcomes between the colchicine and usual care arms in both the primary analysis population and in subgroups, including subgroups based on symptom duration, baseline disease severity, age, or comorbidities.
  • The occurrence of adverse events was similar in the colchicine and usual care arms.

Limitations

  • The design of the study was open-label treatment.
  • The sample size of the colchicine arm was small.

Colchicine in Hospitalized Patients With COVID-19

The RECOVERY Trial

In the RECOVERY trial, hospitalized patients with COVID-19 were randomized to receive colchicine (1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 10 days or until discharge) or usual care.6

Results

  • The study enrolled 11,340 participants.
  • At randomization, 10,603 patients (94%) were receiving corticosteroids.
  • The primary endpoint of all-cause mortality at Day 28 occurred in 1,173 of 5,610 participants (21%) in the colchicine arm and 1,190 of 5,730 participants (21%) in the placebo arm (rate ratio 1.01; 95% CI, 0.93–1.10; P = 0.77).
  • There were no statistically significant differences between the arms for the secondary outcomes of median time to being discharged alive, discharge from the hospital within 28 days, and receipt of mechanical ventilation or death.
  • The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was similar in the 2 arms. Two serious adverse events were attributed to colchicine: 1 case of severe acute kidney injury and one case of rhabdomyolysis.

Limitations

  • The trial’s open-label design may have introduced bias for assessing some of the secondary endpoints.

The GRECCO-19 Trial

GRECCO-19 was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until hospital discharge or for up to 3 weeks) or standard of care alone.7

Results

  • Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50 patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by 2 points on a 7-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
  • Participants in the colchicine group were significantly more likely to experience diarrhea (occurred in 45.5% of participants in the colchicine arm vs. 18.0% in the standard of care arm; P = 0.003).

Limitations

  • The overall sample size and the number of clinical events reported were small.
  • The study design was open-label treatment assignment.

The results of several small randomized trials and retrospective cohort studies that have evaluated various doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-reviewed journals or made available as preliminary, non-peer-reviewed reports.8-11 Some have shown benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies have reported higher discharge rates or fewer deaths among patients who received colchicine than among those who received comparator drugs or placebo. However, the findings of these studies are difficult to interpret due to significant design or methodological limitations, including small sample sizes, open-label designs, and differences in the clinical and demographic characteristics of participants and permitted use of various cotreatments (e.g., remdesivir, corticosteroids) in the treatment arms.

Adverse Effects, Monitoring, and Drug-Drug Interactions

Common adverse effects of colchicine include diarrhea, nausea, vomiting, abdominal cramping and pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by CYP3A4 and P-gp pathways.12,13 Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.

Considerations in Pregnancy

There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent meta-analysis did not find that colchicine exposure during pregnancy increased the rates of miscarriage or major fetal malformations. There are no data for colchicine use in pregnant women with acute COVID-19. Risks of use should be balanced against potential benefits.12,14

Considerations in Children

Colchicine is most commonly used in children to treat periodic fever syndromes and autoinflammatory conditions. Although colchicine is generally considered safe and well tolerated in children, there are no data on the use of the drug to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C).

References

  1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
  2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
  3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2021 May;80(5):550-557. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293273.
  4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9(8):924-932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34051877.
  5. PRINCIPLE Trial Collaborative Group, Dorward J, Yu L, et al. Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.09.20.21263828v1.
  6. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34672950.
  7. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32579195.
  8. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med. 2020;9(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
  9. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
  10. Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33542047.
  11. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
  12. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf.
  13. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for-management-of-clinically-significant-drug. Accessed November 2, 2021.
  14. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29029311.

www.covid19treatmentguidelines.nih.govAn official website of the National Institutes of Health

The Role of Colchicine in Pericardial Syndromes

Authors: George Lazaros 1Massimo Imazio 2Antonio Brucato 3Charalambos Vlachopoulos 1Emilia Lazarou 1Dimitrios Vassilopoulos 4Dimitris Tousoulis 1PMID: 29336245

DOI: 10.2174/1381612824666180116101823 Curr Pharm Des . 2018;24(6):702-709. doi: 10.2174/1381612824666180116101823.

Abstract

Background: Colchicine is an old drug originally employed for the treatment of inflammatory disorders such as acute gout and familiar Mediterranean fever.

Methods: In the past few decades, colchicine has been at the forefront of the pharmacotherapy of several cardiac diseases, including acute and recurrent pericarditis, coronary artery disease, prevention of atrial fibrillation and heart failure. In this review, we have summarized the current evidence based medicine and guidelines recommendations in the specific context of pericardial syndromes.

Results: Colchicine has been firstly engaged in the treatment of recurrent pericarditis of viral, idiopathic and autoimmune origin. Shortly thereafter colchicine use has been expanded to the primary prevention of recurrences in patients with a first episode of pericarditis depicting similarly good results. The acquisition of high quality scientific data in the course of time from prospective randomized placebo-controlled trials and metanalyses have established colchicine as first line treatment option in acute and recurrent pericarditis, on top of the conventional treatment. The only concerns related to the use of colchicine are the side effects (mainly gastrointestinal intolerance) which although generally not serious, may account for treatment withdrawal in some cases.

Conclusion: Colchicine has been established as a first line medication in the treatment of acute (first episode) and recurrent pericarditis on top of the conventional treatment as well as for the prevention of postpericardiotomy syndrome. It depicts a good safety profile with gastrointestinal intolerance being the most common side effect.

Colchicine Treatment for Recurrent Pericarditis

A Decade of Experience

Authors: Y. AdlerY. FinkelsteinJ. GuindoA. Rodriguez de la SernaY. ShoenfeldA. Bayes-GenisA. SagieA. Bayes de Luna and D. H. SpodickOriginally published2 Jun 1998 https://doi.org/10.1161/01.CIR.97.21.2183 Circulation. 1998;97:2183–2185

Abstract

Background—The most troublesome complication of acute pericarditis is recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases. The cause of the recurrence is usually unknown, although in some cases it may be traced to viral infection or may be a consequence of coronary artery bypass grafting. The optimal method for prevention has not been fully established; accepted modalities include nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and pericardiectomy.

Methods and Results—Based on the proven efficacy of colchicine therapy for familial Mediterranean fever (recurrent polyserositis), several small studies have used colchicine successfully to prevent recurrence of acute pericarditis after failure of conventional treatment. Recently, we reported the results from the largest multicenter international study on 51 patients who were treated with colchicine to prevent further relapses and who were followed up for ≤10 years.

Conclusions—In light of new trial data that have accumulated in the past decade, we review the evidence for the efficacy and safety of colchicine for the prevention of recurrent episodes of pericarditis. Clinical and personal experience shows that colchicine may be an extremely promising adjunct to conventional treatment and may ultimately serve as the initial mode of treatment, especially in idiopathic cases.

Acute inflammation of the pericardium is usually of idiopathic etiology, but it may also be secondary to systemic infection, acute myocardial infarction, cardiac contusion, and autoimmune diseases.1

The most troublesome complication of acute pericarditis is the development of recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases.2345 Recurrent pericarditis is, in most cases, idiopathic. The pathophysiological process may involve the immune system6,7: high titers of anti-myocardial antibodies have been found in post–open heart surgery patients with acute pericarditis. The optimal method for preventing recurrences has not been established. Therapeutic modalities are nonspecific and include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressive agents, and pericardiectomy.18 Relapses may also occur during reduction of drug doses (incessant pericarditis) or at varying intervals after discontinuation of treatment (recurrent pericarditis).9 Because treatment is often difficult and recurrences may occur over a period of many years,10 constant efforts are being directed toward establishing better means for prevention. In light of recent trial data, we will review the evidence supporting the use of colchicine in preventing recurrent episodes of pericarditis.

On the basis of proven efficacy of colchicine in preventing relapses of systemic inflammatory processes in familial Mediterranean fever (recurrent polyserositis),1112 Rodriguez de la Serna and colleagues13 suggested in 1987 that colchicine be used to prevent recurrences of acute pericarditis. They reported on 3 patients who had recurrent pericarditis (2 idiopathic and 1 with systemic lupus erythematosus), despite adequate treatment with corticosteroids. All were treated with colchicine (1 mg/d) with tapering of the corticosteroids within 2 months. There were no relapses throughout the follow-up period of 15 to 35 months.

In a later prospective study, Guindo and colleagues14 reported on 9 patients (5 idiopathic, 2 post–open heart surgery, 1 with Dressler’s syndrome, and 1 with systemic lupus erythematosus) in whom NSAIDs and corticosteroids failed to prevent relapses of pericarditis (mean of 4.3 episodes per patient). All were treated with combined prednisone (20 to 60 mg/d), which was tapered and discontinued within 6 weeks, and colchicine (1 mg/d). Chest pain was effectively relieved, and no recurrences of pericarditis were noted within a 10- to 54-month follow-up period.

Adler and coworkers10 reported on 8 patients with recurrent pericarditis (5 idiopathic, 2 post–open heart surgery, 1 post chest trauma) who had not responded to NSAIDs (6 patients), corticosteroids (7 patients), and pericardiocentesis (3 patients). All responded to colchicine (1 mg/d) and corticosteroids. The corticosteroids were discontinued within 2 to 6 months, and no recurrences were noted during the 18 to 34 months of follow-up. This result contrasts with a total of 26 relapses in these 8 patients before the introduction of colchicine. Four patients in whom colchicine had been withdrawn because of noncompliance or mild gastrointestinal side effects experienced a relapse within 1 to 12 weeks. With reinstitution of colchicine therapy, they remained symptom-free for the 15 to 24 months of follow-up.

Millaire and coworkers15 reported on 19 patients who had recurrent pericarditis and were treated with colchicine (loading dose of 3 mg/d, reduced to 1 mg/d). Fourteen had no recurrences during a follow-up period of 32 to 44 months. In 4 others, relapses were successfully treated with NSAIDs, and these patients remained symptom-free for an additional 11 to 37 months. Only 1 patient had multiple relapses and needed corticosteroids. The authors concluded that colchicine was an effective alternative therapy for recurrent pericarditis and might even replace corticosteroids. In another report by Adler et al,16 colchicine totally prevented relapses in 56% of patients with previous episodes (range, 2 to 15 attacks) in a long-term follow-up (mean, 36 months per patient) study, and when relapses did occur, they were usually mild and easily controlled without steroids. These researchers suggested that colchicine might even serve as the initial mode of therapy for recurrent pericarditis, because most of the patients who experienced relapses after the institution of colchicine or its withdrawal were those who had previously been treated with corticosteroids.16 Indeed, several studies have found that corticosteroids may have severe side effects and lead to new recurrences of pericarditis or prolong disease duration.17181920 Thus, colchicine may also have a role in facilitating their tapering-off process.9 Still, some authors doubt the efficacy of colchicine because a double-blind, controlled study on the subject is difficult to perform.21 It was for this reason that Fowler and Harbin22 examined the natural history of recurrent pericarditis to determine the frequency of spontaneous remissions. Of the 31 patients included in their study, only 8 had a remission period that exceeded 1 year; in 5 of the 8, remission exceeded 2 years.

A partial answer to these doubts may be found in the largest multicenter study on recurrent pericarditis and colchicine published to date.23 Fifty-one affected patients (36 men and 15 women; mean±SD age, 40.8±18.7 years) who were treated with colchicine to prevent further relapses were followed up for ≤10 years (range, 6 to 128 months; mean, 36.0 months). The pericarditis was idiopathic in 33 patients and secondary in 18. Despite treatment with NSAIDs (n=47), corticosteroids (n=29), pericardiocentesis (n=8), or some combination thereof, 187 recurrences (mean, 3.58±3.64; range, 2 to 15) were noted before colchicine therapy was initiated, with a mean interval between crises of 2.0 months (range, 0.5 to 19 months). During 1004 patient-months of colchicine treatment, only 7 of 51 patients (13.7%) presented with new recurrences. Colchicine was discontinued in 39 patients, and 14 of them (35.8%) experienced relapses. These recurrences were generally minor and were effectively controlled in all patients by the reinstitution of colchicine therapy, sometimes with a dose adjustment of the drug (≤2 mg/d). Gastrointestinal side effects were mild (diarrhea and nausea) and resolved in all patients. During the 2333 patient-months of follow-up, 31 patients (60.7%) remained recurrence-free. Comparison of the symptom-free periods before and after colchicine treatment yielded significant statistical differences (3.1±3.3 versus 43.0±35.0 months, P<0.0001). The authors concluded that colchicine was effective and safe for the long-term prevention of recurrent pericarditis.

The exact mechanism whereby colchicine prevents recurrences of pericarditis is still not fully understood. Colchicine has been used for several centuries as an anti-inflammatory agent for acute arthritis and is the most specific known treatment for acute attacks of gout. Colchicine binds to tubulin, blocks mitosis,9 and inhibits a variety of functions of polymorphonuclear leukocytes both in vivo and in vitro.24 Colchicine also interferes with the transcellular movement of collagen.25 The close proximity of lymphoid components and fibroblasts at inflammatory sites and the production of lymphokines, which influence fibroblast chemotaxis, proliferation, and protein synthesis, are now well recognized.26 Thus, colchicine may reduce immunopathic antifibroblastic properties. The peak concentration of colchicine in white blood cells may be ≥16 times the peak concentration in plasma. This preferential concentration of colchicine in lymphocytes is related to its observed therapeutic effect.27

Cumulative anecdotal evidence indicates that colchicine may also be effective in the treatment of the initial episodes of acute pericarditis. Millaire and Durlaux,28 in a study of 19 patients, described the efficacy of colchicine for the first episode of acute pericarditis, especially when it was idiopathic, viral, or post–open heart surgery. Colchicine effectively controlled the acute phase of pericarditis in almost all cases. Only two relapses were noted in a mean follow-up period of 5 months (range, 1 to 12 months), one due to discontinuation of treatment after 8 days and the other due to noncompliance.

Recently, we examined the usefulness of colchicine for the treatment of large pericardial effusions as complications of idiopathic pericarditis.29 Colchicine (1 mg/d) was administered to two patients (26 and 2 years old) with large acute or chronic pericardial effusions who did not respond well to therapy with NSAIDs, corticosteroids, and pericardiocentesis. Response was immediate and dramatic in both cases, with disappearance of the pericardial effusion on echocardiography. Neither patient suffered a relapse during the respective 24 and 6 months of follow-up.

In addition to its apparently greater efficacy compared with corticosteroids,916 colchicine may also have a sparing effect on steroids, which have severe systemic side effects over time and may prolong disease duration.17181920 Furthermore, immunosuppressive drugs and pericardiectomy are generally not appropriate and may even be life threatening,21 whereas colchicine is usually well tolerated, with only minor side effects. During a total of 1004 patient-months of colchicine treatment (mean, 12 months per patient), temporary discontinuation of the drug or a reduction of its dose was needed in only 7 of 51 patients (13.7%).23 This was due to mild gastrointestinal side effects (diarrhea and nausea) in all cases, which are the common drawbacks of colchicine therapy. Drug toxicity with respect to long-term administration of colchicine might be estimated from familial Mediterranean fever or gout patients. Azoospermia and chromosomal abnormalities have been reported with long-term treatment,30 but these findings are debatable.

In conclusion, colchicine seems to be an effective and safe agent for the prevention of recurrent episodes of pericarditis. Colchicine is an extremely promising adjunct to the conventional treatment of recurrent pericarditis and may ultimately serve as the initial mode of treatment, especially in idiopathic cases. Considering that recurrent pericarditis is not life threatening and that long-term treatment is aimed at improving the quality of life, we suggest that corticosteroids should be limited to very severe cases. Milder cases may initially be treated with colchicine as well as with NSAIDs (ibuprofen). The recommended dose of colchicine according to most studies is 1 mg/d for at least 1 year, with a gradual tapering off. The need for a loading dose of 2 to 3 mg/d at the beginning of treatment is unclear. The drug is well tolerated. Gastrointestinal side effects develop in only a small proportion of patients, are usually minor, and do not require discontinuation of treatment in most cases.

Despite the promising data on the efficacy and safety of colchicine for recurrent pericarditis that have accumulated in the past decade, large, controlled, prospective studies are required to provide definitive answers on the subject.

We thank Gloria Ginzach, Marian Propp, and Charlotte Sacks for their editorial and secretarial assistance.

Footnotes

Correspondence to Y. Adler, MD, Department of Cardiology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, 49100, Israel.

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Colchicine could cut COVID-19 deaths – Israeli scientist

Authors: By MAAYAN JAFFE-HOFFMAN Published: DECEMBER 14, 2021 17:37

An ancient Greek drug derived from the saffron plant could improve the treatment of people with severe COVID-19 and reduce the COVID mortality rate by as much as 50%, according to a report published earlier this month in the European Journal of Internal Medicine by an Israeli researcher from the Hebrew University of Jerusalem and Hadassah Medical School. The drug, colchicine, dates back thousands of years to ancient Egypt, where it was known for its special healing properties. It is one of a few medicines that survived until modern times. Most recently, it has been used to treat and prevent inflammation caused by gout that can lead to painful arthritis and Familial Mediterranean Fever (FMF), which is common among Jewish people of North African descent.

Prof. Ami Schattner researched and analyzed all patients treated in controlled trials of this ancient drug for the past 20 years. He found that among its uses and potential uses, colchicine also appears effective in treating COVID-19.So far, four controlled studies of around 6,000 coronavirus patients have been published on the effect of colchicine, Schattner said, each showing a “significant improvement in severe coronavirus indices and, most importantly, there was a decrease in mortality by about 50% compared to those who were not treated with colchicine. ”The drug is cheap, a small half-milligram dose is needed per day, and it has already been proven safe to use, he said, making colchicine “an important discovery that could significantly contribute to improving the morbidity and mortality of many patients, if confirmed in further studies.”

The drug is also well-tolerated, the doctor said. The only side-effects in some patients can be bouts of diarrhea; about 10% of patients discontinue the use of the drug for this reason. The drug has been tested in the treatment of the COVID-19 pandemic around the world, including in Canada, Greece, South Africa, Spain and Brazil. Many of the tests were double-blind placebo studies, increasing their likelihood of accuracy. “The results were impressive,” he said. Colchicine was first mentioned in an ancient Egyptian papyrus dating back to 1550 BC, even before the Jewish people left Egypt, according to the biblical story. Later, it was used by physicians in ancient Greece, in the Byzantine period and then by Arab physicians more than 1,000 years ago. Some 50 years ago, using the drug to treat FMF was verified by researchers at Sheba Medical Center at Tel Hashomer and Hadassah, not only against the sharp attacks associated with the disease and their prevention, but also in protection against a serious complication of FMF – amyloidosis, which affects the kidneys. More recently, several studies have started to prove its effectiveness in the treatment of acute pericarditis (swelling around the heart, and in the prevention of post-cardiac injury syndrome and atrial fibrillation following cardiac surgery.“As is well known, patients who have had a heart attack are at a significantly increased risk of recurrence and stroke, and these are very many patients,” Schattner said. “Studies from recent years have found that thanks to its anti-inflammatory activity on the atherosclerotic layers in the arteries, colchicine in small daily doses is able to effectively protect these patients. “The level of protection was to the point of preventing about half of the recurrent events, and this impressive beneficial effect was also achieved in patients who had already undergone therapeutic catheterization and had taken optimal preventive treatment by aspirin and statins,” he added. “This is important news for a very large number of patients.”

Further randomized controlled trials are needed to confirm these preliminary results, according to Schattner, which he believes will likely lead to expanding indications for low-dose colchicine. But he said there is no reason that the drug could not start being used right now.“Even though initial data on the effect of colchicine on coronavirus patients is very promising, more patients need to be in randomized controlled trials,” Schattner said. “But that would not prevent me from using the drug already in patients with high risk, to hopefully lower their chances of developing severe disease.“The drug is low-cost for the patients and the community,” he continued. “By using it in corona patients, we have nothing to lose and much to gain.”

COVID-19 also attacks the pancreas; one vaccine dose may be enough for those previously infected

Authors: Nancy Lapid February 3, 2021

COVID-19 attacks the pancreas

The new coronavirus directly targets the pancreas, infecting and damaging its insulin producing cells, according to a new study. The findings may help explain why blood sugar problems develop in many COVID-19 patients, and why there have been reports of diabetes developing as a result of the virus. The pancreas has two jobs: production of enzymes important to digestion, and creation and release of the hormones insulin and glucagon that regulate blood sugar levels. In a paper published on Wednesday in Nature Metabolism, researchers report that lab and autopsy studies show the new coronavirus infects pancreas cells involved in these processes and changes their shape, disturbs their genes, and impairs their function. The new data “identify the human pancreas as a target of SARS-CoV-2 infection and suggest that beta-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19,” the authors conclude. (https://go.nature.com/36Cmtfy)

One vaccine dose might be enough for COVID-19 survivors

COVID-19 survivors might only need one shot of the new vaccines from Moderna Inc and Pfizer/BioNTech, instead of the usual two doses, because their immune systems have gotten a head start on learning to recognize the virus, according to two separate reports posted this week on medRxiv ahead of peer review. In one study of 59 healthcare workers who recovered from COVID-19 and received one of the vaccines, antibody levels after the first shot were higher than levels usually seen after two doses in people without a history of COVID-19. In a separate study, researchers found that 41 COVID-19 survivors developed “high antibody titers within days of vaccination,” and those levels were 10 to 20 times higher than in uninfected, unvaccinated volunteers after just one vaccine dose. “The antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds” levels found in uninfected individuals after the second vaccine dose, the authors of that paper said. “Changing the policy to give these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses,” they said. (https://bit.ly/3je4Zv4; https://bit.ly/2YG0EYf)

Gout drug shows promise for mildly ill COVID-19 patients

Colchicine, an anti-inflammatory drug used to treat gout and other rheumatic diseases, reduced hospitalizations and deaths by more than 20% in COVID-19 patients in a large international trial. COVID-19 patients with mild illness and at least one condition that put them at high risk for complications, such as diabetes or heart disease, received either colchicine or a placebo for 30 days. Overall, the risk of hospitalization or death was statistically similar in the two groups. But among the 4,159 patients whose coronavirus infections had been diagnosed with a gold-standard PCR test, death or hospital admission occurred in 4.6% of those on colchicine versus 60% of those who got a placebo. After taking patients’ other risk factors into account, colchicine was associated with a statistically significant 25% risk reduction, the researchers reported on medRxiv ahead of peer review. Patients taking colchicine also had fewer cases of pneumonia. “Given that colchicine is inexpensive, taken by mouth, was generally safe in this study, and does not generally need lab monitoring during use, it shows potential as the first oral drug to treat COVID-19 in the outpatient setting,” the researchers said. (https://bit.ly/3oDSDgY)

Oxford/AstraZeneca vaccine might work better with doses months apart

Among recipients of the COVID-19 vaccine from Oxford University and AstraZeneca, prolonging the interval between the first and second doses led to better results, researchers said in a paper posted on Monday ahead of peer-review by The Lancet on its preprint site. For volunteers aged 18 to 55, vaccine efficacy was 82.4% with 12 or more weeks between doses, compared to 54.9% when the booster was given within 6 weeks after the first dose. The longest interval between doses given to older volunteers was 8 weeks, so there were no data for the efficacy of a 12-week dosing gap in that group. Europe’s medicine regulator has said there is not enough data to determine how well the vaccine will work in people over 55. Given their findings, the authors say “a second dose given after a three-month period is an effective strategy … and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term.”